This Program Project Renewal is directed at establishing the mechanisms which control normal B cell development and at identifying the causes of B cell immune deficiencies and malignancies. Four interactive research projects comprise the scientific components of this Program Project on Immune Function and Cancer. Dr. Randolph Wall leads the B Cell Genes: Expression, Regulation and Function, which is directed at identifying regulatory genes that control B cell-specific transcription. Other supplies on this project will analyze C cell gene translocations in chronic lymphocytic leukemia (CLL). These studies are expected to reveal new insights into early B cell gene activation and into the commitment of progenitor cells to the B lineage. Dr. Owen Whitte is the Project Leader on Pre-Clinical Model for Gene Therapy of X-linked Agamma- globulinemia, which is aimed at developing an experimental system for overcoming the genetic defects in the critical B cell tyrosine kinase, BTTK, which cause XLA in human B cells. These gene replacement studies represent an important advance towards the eventual treatment of other human immune deficiencies caused by genetic defects. Dr. Jon Braun heads the studies on Mechanisms of Human B-Cell Selection and V Gene Diversification, which are directed at characterizing VH region hypermutation mechanisms and at establishing the nature and immunological consequences of HIV gp 120 binding to VH3 immunoglobulins. These latter studies should provide insights into the origins of the B cell lymphomas in HIV infections. Dr. Andrew Saxon directs Regulation of B-cell differentiation in Common Variable Immunodeficiency Patients Whose B- cells Respond to CD40 Plus IL-4, which is aimed at identifying the intrinsic molecular defects that block B cell differentiation to immunoglobulin secretion in common variable immunodeficiency (CVI) CVI B cells from certain patients stimulated with anti-CD40 plus IL-4, have been shown to bypass this block to differentiation. These studies will exploit these CVI cells to identify the genes and critical signaling events affected in CVI. Administrative Core headed by Dr. Wall (Program Project P.I.) and Dr. Saxon (Co-P.I.) manages accounting and interdepartmental matters for the Program Project.